This application is a competing continuation of a Program Project originally funded in April 1995. The project is based on several key findings indicating that growth hormone and IGF-1 not only have an important effect on aging of peripheral tissues, but that these hormones also contribute to functional and structural changes within the brain, which eventually lead to a cognitive decline. The hypothesis of this application is that deficits in growth hormone and IGF-1 decrease cerebrovasculature and blood flow and attenuate an active remodeling process resulting in deficiencies in neuronal function and increased oxidative stress. These changes, either alone or in concert, lead to structural and cognitive alterations in the aging brain and increase risk of the aging brain for disease processes. Project 1 (W. E. Sonntag) will assess the consequences of growth hormone deficiency on local cerebral blood flow and vascular density and the relationship between the age-related decrease in vascular parameters, increased oxidative stress and the decline in neuronal activity. The hypothesis that growth hormone and IGF-1 protect against oxidative stress induced decreases in vascular density, blood flow, and neuronal activity also will be assessed. Project 2 (D. R. Riddle) will test key predictions of the hypothesis that IGF-1 regulates neurogenesis and plays a critical role in the response of the central nervous system to oxidative stress. Project 3 (J. K. Brunso-Bechtold) will investigate whether IGF-1 deficiency alone or in combination with accumulated oxidative stress across the lifespan are critical factors in the age-related loss of synapses and/or dendritic spines and whether increased IGF-1 levels will protect synapses and dendritic spines from the biological effects of oxidative stress. A unique aspect of this application is that the projects will incorporate an animal model of adult-onset growth hormone deficiency (validated in the current funding period). This model will permit us to evaluate the specific actions of growth hormone and IGF-1 apart from pathological or secondary age-related changes in the CNS. This program project will provide valuable information on potential mechanisms that contribute to vascular dementia and increased susceptibility to diseases commonly observed in the elderly.